Fig. 5. AMPK plays a central role as a tumor suppressor. AMPK inhibits de novo lipid/cholesterol synthesis through inhibiting ACC and HMGCR to dampen tumor cell proliferation. It also represses SREBP-1c and ChREBP that induce ACC and fatty acid synthase. AMPK also induces aberrant glycosylation of PD-L1 by phosphorylating at S195 of PD-L1, leading to ER-associated protein degradation (ERAD). In context of mTORC1, AMPK inhibits TSC2 to prevent Rheb from GTP binding. AMPK also hinders Raptor, which reduce the activity of 4EBP1 and S6 kinases. Oncogenic AKT is inhibited by AMPK-induced phosphatase A2. In other aspect, AMPK activates tumor suppressor genes. AMPK phosphorylates p53 at Ser-15 and -46, then it activates p21 and Bax to arrest tumor cell proliferation. another tumor suppressor FOXO3a is phosphorylated by AMPK. This leads to apoptotic genes such as Fas ligand, TRAIL, and Bcl-2 to induce tumor cell death. The figure is created with BioRender.com.
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